multiple sclerosis aetiology,pathology,diagnosis,differential diagnosis and management

1. Multiple sclerosis
OSAMA RAGAB

2. introduction
Multiple sclerosis (MS) is a chronic inflammatory disease of the central
nervous system (CNS) characterized by the breakdown of the insulating
myelin sheath that covers the nerve axons in the CNS and subsequent
degeneration of axons.
MS affects approximately 400,000 people in the USA and more than 2.1
million people worldwide, but the incidence has increased in the last five
decades, particularly in women (3.6/100,000 person /years) compared to
men (2.0/100,000 person /years)

3. introduction
Etiology
1. Genetic
2. autoimmunity
3. Infection
4. Vitamin D
5. Cerebral venous insufficiency
6. Loss of old friends

4. Genetics
 The major histocompatibility complex (MHC) region on chromosome
6p21.32 is the first identified MS risk locus.
 HLA-DRB1*1501 allele conferring a ~3-fold risk increase. As well as
DRB1*1303 conferred further risk.
 IL7RA(encoding the interleukin receptor 7A) was initially assessed and
reported as a putative MS risk gene.
 IL2Rα were found to be significantly associated with relatively risk of
MS.
 CYP27B1, a gene associated with vitamin D metabolism.

5. Genetics
 On the other hand, HLA-DRB1*14 carries such a protective effect that it
completely abrogates the increased risk of HLA-DRB1*15.
 GWAS implicate genes coding for cytokine pathways (CXCR5, IL-2RA, IL-
7R, IL-7, IL-12RB1, IL-22RA2, IL-12A, IL-12B, IRF8, TNFRSF1A,
TNFRSF14, TNFSF14) .
 Costimulatory (CD37, CD40, CD58, CD80, CD86, CLECL1) and signal
transduction (CBLB, GPR65, MALT1, RGS1, STAT3, TAGAP, TYK2).

6. Autoimmunity

7. Autoimmunity

8. Infection
little direct evidence supports the concept of a role for viral infection.
Innumerable efforts to culture a virus from autopsy-derived or biopsy
material have yielded no consistent result.
human T-cell lymphotropic virus type 1 [HTLV1]) have proven negative.
Human herpesvirus 6 (HHV6), Epstein-Barr virus (EBV), and Chlamydia
pneumoniae have been the focus of interest.
High serum levels of EBV antibodies have also been associated with an
increased risk of MS.

9. Geographical distribution of MS

10. Vitamin D
MS patients typically have lower serum 25(OH)D levels than healthy controls .
Polymorphisms in the vitamin D receptor (VDR) gene have been of particular
interest.
candidate gene approach include two vitamin D metabolism-related genes,
CYP2R1 [which encodes the enzyme responsible for the conversion of vitamin
D to 25(OH)D] and DBP/GC (encoding the vitamin D-binding protein)
these inverse associations could also be explained by a direct effect of UVB
radiation, which has immunosuppressive effects independent from vitamin D.

11. Venous insufficiency
Zamboni and colleagues proposed that multiple sclerosis is caused by
abnormalities in the direction and pathway of cerebral venous flow, leading to
deposition of iron in the brain, which triggers an autoimmune reaction.
They reported that patients with multiple sclerosis had a higher frequency of
abnormalities of anatomy and flow in the internal jugular, deep cerebral,
vertebral and azygous veins than individuals without multiple sclerosis had.

12. Venous insufficiency

13. Loss of old friends
Leibowitz and co-workers proposed that the prevalence of MS was linked
to a high sanitation level during childhood.
Epidemiological data demonstrating an inverse relationship between the
prevalence of autoimmune diseases and parasite infections, and more
specifically between MS and the helminth Trichuris trichuria.
There is decrease production of IL-12, TNF-α and IL-1β and increased
production of TGF-β and IL-10 in peripheral blood mononuclear cells
(PBMC's) and increased proliferation of CD4+CD25high regulatory T-cells
(Tregs) in infected person.

14. Loss of old friends

15. Clinical picture
patients may be grouped into four major categories based on the course of
disease:
1.Relapsing–remitting MS: the most common form, affecting about 85% of
MS patients.
2.Secondary progressive MS: may develop in some patients with
relapsing–remitting disease
3.Primary progressive MS: affects approximately 10% of MS patients.
Symptoms continue to worsen gradually from the beginning.
4.Progressive-relapsing MS: a rare form, affecting fewer than 5% of
patients. It is progressive from the start, with intermittent flare-ups of
worsening symptoms along the way.

17. Clinical picture

18. Clinical picture

19. Clinical picture

20. What Is the Composition of the MS Plaque
Multiple sclerosis plaques may be characterized as active or inactive .
Macrophages are especially plentiful in active lesions which are
hypercellular and contain patchy infiltrates of autoreactive T cells and
antigen-nonspecific monocytes and macrophages within a zone of myelin
loss .
Macrophages and lymphocytes form prominent perivascular cuffs and
invade the parenchyma, whereas plasma cells and B cells tend to
concentrate in the perivascular region only

21. What Is the Composition of the MS Plaque
Chronic plaques display well-demarcated areas of hypocellularity with
myelin pallor or loss .
There are varying degrees of axonal loss, usually most obvious in the
lesional center .
There is typically a persistent but minor inflammatory response.
There are few or no oligodendrocytes.

22. Clinical picture
Cognitive Impairment.
34% to 65% of patients with MS have cognitive impairment.
The domains of verbal memory and attention/speed of information
processing were the most affected.
Comorbid depression, anxiety disorders, and emotional lability may
further affect cognitive performance.
Lesions located in frontal and parietal lobes showed stronger correlations
with tasks of processing speed, attention, and verbal memory.

23. Clinical picture
Affective Disorders.
Depression is the most common manifestation and is in part secondary to
the burden of having to cope with a chronic disease.
Suicide rates are higher in patients with MS than in the general population.
emotional “dyscontrol” is quite common, and patients oscillate frequently
between sad and happy states, at times without precipitant.

24. Clinical picture
Impairment of Visual Pathways
Optic neuritis (ON) is the most frequent type of involvement of the visual
pathways, usually presenting as an acute or subacute unilateral syndrome.
Bilateral simultaneous ON is rare in MS.
The Uhthoff phenomenon refers to a recurrence of a neurological
symptom (e.g., visual blurring) following an increase in body temperature.

25. Clinical picture
Impairment of Ocular Motor Pathways
the involved nerves are, in decreasing order of frequency, cranial nerves
VI, III, and (rarely) IV.
acquired pendular nystagmus, in which there are rapid small-amplitude
pendular oscillations of the eyes in the primary position, resembling
quivering jelly.
Internuclear ophthalmoplegia (INO), Convergence is preserved. When
present bilaterally, it is usually coupled with vertical nystagmus on upward
gaze.
One and half syndrome.

26. Clinical picture
Impairment of Other Cranial Nerves.
Facial myokymia, a fine, undulating wavelike facial twitching, and
hemifacial spasm.
Unilateral facial paresis can occur, but taste sensation is almost never
affected.
Vertigo is a reported symptom in 30% to 50% of patients with MS and is
commonly associated with dysfunction of adjacent brainstem or cranial
nerves.
Malfunction of the lower cranial nerves is usually of the upper motor
neuron type (pseudobulbar syndrome)

27. Clinical picture
Impairment of Sensory Pathways
The sensory features can reflect spinothalamic, posterior column, or
dorsal root entry zone lesions. The sensory symptoms are commonly
described as numbness, tingling, pins and needles.
The most frequent sensory abnormalities on clinical examination are
varying degrees of impairment of vibration and joint position sense.
Brown-Séquard syndrome.
the “numbclumsy hand” syndrome is a characteristic but uncommon

28. Clinical picture
Impairment of Motor Pathways.
Paraparesis or paraplegia occurs more frequently than significant
weakness in the upper extremities.
Amyotrophy, when observed, most frequently affects the small muscles of
the hand; lesions of the motor root exit zones may produce muscle
denervation secondary to axon loss.

29. Clinical picture
Impairment of Cerebellar Pathways
gait imbalance, difficulty performing coordinated actions with the arms,
and slurred speech.
dysmetria, decomposition of complex movements, and hypotonia, most
often observed in the upper extremities.
An intention tremor
Ocular findings of nystagmus, ocular dysmetria, and frequent refixation
saccades.
Speech can be scanning or explosive in character.
In severe cases, complete astasia (inability to stand),

30. Clinical picture
Impairment of Bladder, Bowel, and Sexual Functions
urinary urgency, usually the result of uninhibited detrusor contraction,
reflecting a suprasegmental lesion.
As the disease progresses, urinary incontinence due to urgency becomes
more frequent.
With involvement of sacral segments of the spinal cord, symptoms of
bladder hypoactivity may evolve (e.g., decreased urinary flow, interrupted
micturition, incomplete bladder emptying).

31. Clinical picture
Impairment of Bladder, Bowel, and Sexual Functions
An atonic dilated bladder that empties by overflow results from loss of
perception of bladder.
A dyssynergic voluntary sphincter that interrupts bladder emptying will lead to
frequent, small-volume urinations combined with a large postvoid residual.
Constipation is more common than fecal incontinence.
Sexual dysfunction, although frequently overlooked, occurs commonly in MS.
Approximately 50% of patients become completely sexually inactive because of
their disease, and an additional 20% become less sexually active.

32. Tumefactive MS
Tumefactive MS is an acute tumor-like MS variant in which some patients
with demyelinating disease present with large (>2 cm) acute lesions, often
associated with edema or ring enhancement .
There may be mass effect, with compression of the lateral ventricle and
shift across the midline. Although there is no consensus regarding
nomenclature.

33. Tumefactive MS
The clinical abnormalities in such patients are variable; they may be very
slight even in a patient with a massive lesion, while confusion,
hemiparesis, or neglect syndrome can be seen in another patient with a
lesion that appears no different.
Typically, much of the T2-bright lesion volume on brain MRI is due to
edema and may be rapidly responsive to glucocorticoid treatment.
However, radiologic improvement with glucocorticoids can also occur with
glioma or with central nervous system lymphoma and is therefore not a
useful diagnostic criterion.
Biopsy is often required.

34. Clinical picture

35. Clinical picture

36. Clinical picture
Prognosis.
 Sex: benign course in women than in men.
 Age at onset: Average is 29 to 32 years. Onset at an early age is a
favorable factor, whereas onset at a later age carries a less favourable.
 Initial disease course: Relapsing form of the disease is associated with a
better prognosis than progressive disease
 Initial complaints: impairment of sensory pathways or ON has been
found in several studies to be a favorable prognostic feature, whereas
pyramidal and particularly brainstem and cerebellar symptoms carry a
poor prognosis.

37. Magnetic resonance imaging

38. 3 of 4
 1 Gd+ or 9 T2-hyperintense lesions if there is no enhancing lesion
 At least one infratentorial lesion
 At least one juxtacortical lesion
 At least 3 periventricular lesions
MRI criteria dissemination in space
Barkhof et al criteria

52. MAGNETIC RESONANCE SPECTROSCOPY
In active, newly formed MS plaques, NAA is slightly decreased and Cre,
Cho, and mI are increased. Lactate (Lac) peak is also increased,
suggesting energy failure. Over time, the initial surge in lipids, Cho, Lac,
and Cre may return to near normal.
In contrast to active plaques, chronic MS lesions show considerable
reduction in NAA, normal glutamate peaks, and elevation in mI.
Interestingly

55. Magnetization Transfer Imaging
Demyelination is visualized as a reduced proton exchange, or a decrease
in the magnetization transfer ratio (MTR), whereas an elevated proton
exchange, or increased MTR, is evidence of possible remyelination or
resolution of edema.

57. Diffusion tensor imaging
Diffusion tensor imaging allows measurement of fractional anisotropy,
which reflects the degree to which the diffusion of water molecules follows
one direction versus many directions.
This technique is useful for assessing the integrity of white matter tracts,
which normally have a high degree of anisotropy due to their linear
arrangement and the preferred diffusion of water along the long axis of the
myelinated fibers .
Injury to nerve axons or myelin sheaths permits increased diffusion of
water across the white matter tract and thereby decreases fractional
anisotropy

58. Diffusion tensor imaging
Axial flair image (A) show two plaques in the internal capsule, one in the anterior
limb and one in the posterior limb. Diffusion tensor fractional anisotropy map (B)
shows asymmetric hypointensity (decreased anisotropy) in these regions

59. Cerebrospinal fluid analysis
The CSF appearance and pressure are grossly normal in MS.
The total leukocyte count is normal in two-thirds of patients, exceeds 15
cells/microL in <5 percent, and only rarely exceeds 50 cells/microL (a
finding that should raise suspicion of another etiology).
Lymphocytes are the predominant cell type, the vast majority of which are
T cells.
CSF protein (or albumin) level is usually normal.

60. Cerebrospinal fluid analysis
An abnormality of CSF IgG production as measured by the IgG index or IgG
synthesis rate is found in 90 percent of clinically definite MS patients .
Oligoclonal bands — OCBs are found in up to 95 percent of patients with
clinically definite MS .
OCBs represent limited classes of antibodies that are depicted as discrete bands
on agarose gel.
The presence of OCBs is not equivalent to a diagnosis of MS.
Antimyelin antibodies — Initial studies suggested that antibodies to myelin
oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) were
potential markers of MS .However, subsequent evidence suggests that these
antibodies are not associated with an increased risk of progression to MS or
with MS disease activi

61. Isoelectric focusing in an agarose gel at stable
pH (range 5.0–9.5) demonstrating the presence
of oligoclonal bands (arrows) in the CSF
(above) and not the serum (below).
The oligoclonal bands are different clones of
IgG that have migrated electrophoretically in
the stationary pH gradient until a steady state is
reached.
To be positive, two or more oligoclonal bands
must be detected in the CSF that are not present
in the serum of the patient.

63. Evoked potentials
Evoked potentials are the electrical events generated in the central
nervous system by peripheral stimulation of a sensory organ.
The three most frequently used evoked potentials are somatosensory
evoked potentials (SSEP), visual evoked responses (VER), and brainstem
auditory evoked potentials (BAEP). Patients with clinically definite MS
have abnormal VERs in 50 to 90 percent of cases .

66. Treatment
IVMP 20 to 30 mg/kg/day for 5 days. A subsequent oral tapering
should be restricted to patients with:-
i) insufficient resolution of symptoms after steroid.
ii) recurrence of symptoms after steroid discontinuation.
Steroid tapering continued usually not exceeding 2 to 3 weeks .
I- Treatment of relapses:
1) Corticosteroids:

67. 3) IV immunoglobulins: IVIg 0.4 g/kg
daily for 5 days in acute demyelinating
attacks that do not improve after high dose
of steroid ‫.٭‬
2) Plasma exchange: indicated in
i) Life-threatening acute demyelination.
ii) Recurrence of symptoms during or
after steroid therapy‫٭٭‬ .

68. Management

69. Management

70. Management

71. Management

73. Oral medication
 Fingolimod ( 0,5 mg daily ) act on s1p receptor prevent egress of activated
lymphocyte to circulation from lymph node.
 Fumaric acid ( 240 mg twice) it activate transcriptional factor nrf2.
 Teriflunamide ( 14 mg ) inhibit pyrimidine synthesis.
 Cladribine ( 0.07 mg / kg ) purine nuclside analogue.
 Laquinamide ( 0.6 mg ) shift Th1 to Th2 response

74. Monoclonal antibodies
 Natalizumab ( 300 mg /28 day ) act on integrin ( VLA4) .
 Rituximab ( 375mg /m²/week ) for 2 months , act on CD2O of B cells.
 Daclizumab act on CD25 of both T&B cells.
 Almetuzumab act on CD52 of both T& B cells.
 Ocrelizumab act on CD20 .
 Mastinab it bind to tyrosine kinase of mast cells

75. Chemotherapy
Cyclophosphamide
The therapy may be administered orally( 1.5 mg/kg) or intravenously.
The most widely used regimen is monthly pulsed therapy with 800 mg/m2
administered monthly for 1 year, followed by bimonthly treatments in those who
are responders, although numerous other regimens have been proposed,
including the use of combined treatment with methylprednisolone.
Dose adjustments are made based on the peripheral white blood cell (WBC) nadir
acquired on the 14th day following treatment The rationale of this adjustment is
to attenuate the peripheral WBC counts with levels between 1500 and 2000
WBC/mm3.

76. Chemotherapy
METHOTREXATE
Methotrexate inhibits dihydrofolate reductase, an enzyme responsible for the
conversion of dihydrofolate into tetrahydrofolate. Tetrahydrofolate and its
derivatives are essential for purine and thymidylate synthesis and cell
proliferation and growth.
Dose 7.5 mg / week IM.

77. Chemotherapy
AZATHIOPRINE
In some instances,considered as a first-line treatment for those unwilling to use
IFN-b or glatiramer acetate, despite somewhat conflicting data.
The medication targets activation, proliferation, and differentiation of fast-
growing cells, including T and B cells, through inhibition of purine synthesis.
Dose up to 2.5 mg /kg daily.

78. Symptomatic treatment
Spasticity
• Attend to any factors which may exacerbate spasticity, such as noxious
stimuli due to urinary tract infection, infected pressure sores or ulcers,
tight clothing, or an uncomfortable orthotic.
• Educate patients to understand and manage their spasticity.
• Correct posture: avoid positions which favor the pattern of spasticity.
• Physiotherapy

79. Pharmacology:
Oral agents:
–– Tizanidine, an L2 alpha adrenergic antagonist.
–– Baclofen, 5 mg bd, increasing slowly to 10–25 mg three times daily if
tolerated and required
–– Diazepam 5–10 mg three times daily.
–– Dantrolene.
–– Gabapentin.
• Intramuscular injections of botulinum toxin A
• Intrathecal baclofen: • Rarely, nerve blocks are used
Symptomatic treatment

80. Bladder dysfunction
• Detrusor hyper-reflexia:
• Clean intermittent self-catheterization (CISC) is the most effective.
• Anticholinergic agents (reduce urgency but may increase residual volume):
–– Oxybutynin hydrochloride 5 mg tablets,
25–5.0 mg every 6–8 hours.
–– Propantheline bromide 15 mg, four times daily.
–– Amitriptyline 25–100 mg daily.
• Intravesical botulinum toxin is an increasingly promising technique.
Symptomatic treatment

81. Fatigue
• Psychologic counseling.
• Amantadine 100 mg in the morning and afternoon can help in some
cases.
• 4-Aminopyridine (fampridine), and 3-4-diaminopyridine, a potassium
channel blocking agent, may have a role.
Symptomatic treatment

82. Tremors and Ataxia
• Clonazepam 0.5–2.0 mg two or three times daily.
• Ondansetron, a 5-hydroxytryptophan-3 (5-HT3) antagonist, 8 mg IV.
• Carbamazepine.
• Gabapentin.
• Isoniazid and pyridoxine.
• Propranolol.
• Buspirone.
• Surgery. Deep brain stimulation appears promising for tremor, but not
ataxia, in MS.
Symptomatic treatment

83. Cognitive dysfunction and depression
in some cases, cognitive rehabilitation.
There is emerging evidence for acetylcholinesterase inhibitors such as
donepezil.
The treatment of depression is similar to that of a patient who does not
have MS, and includes psychologic counseling and serotonin reuptake
inhibitors such as tricyclic antidepressants. However, particular attention
needs to be paid to adverse effects, as they may exaggerate existing
problems such as sexual dysfunction.
Symptomatic treatment

84. Visual dysfunction
• Monocular blindness or scotoma, diplopia and oscillopsia: this is difficult
to manage, but referral to low vision clinics can be helpful.
• Botulinum toxin injections of oculomotor muscles may reduce persistent
oscillopsia.
• Acquired pendular nystagmus may respond to converging prisms and
isoniazid (and possibly gabapentin).
Symptomatic treatment